Diabetes mellitus and related metabolic syndrome represent perhaps the fastest growing major disease market in the developing world. Diabetes has recently been described as "a global pandemic" that affects nearly 200 million people worldwide and costs this country more than $130 billion. Diabetes is a chronic disease characterized by a series of metabolic defects that stem from a failure to adapt correctly to changing blood sugar levels. The result is a series of defects including neuropathies, nephropathy, and a significant increase in the risk of cardiovascular disease. Both basic research and large-scale human trials suggest that most of these problems are linked to the toxic effects of high circulating levels of glucose, or 'glucose toxicity'. While numerous attempts have been made to identify new drugs to combat glucose toxicity, clinical trials have failed due to poor efficacy or high toxicity. Effective treatments for diabetes and glucose toxicity remain one of the largest unmet needs in the health marketplace. One difficulty of diabetes drug discovery is that few models exist that screen in the context of whole animals. Instead, cell culture and related models are commonly used to focus on specific aspects of glucose toxicity. However, the body's energy metabolism is constructed of a complex web of systems, and altering one aspect of this web typically leads to problems elsewhere. A whole animal screening approach would be ideal. Medros (Medicine from Drosophila) was founded on the basis of a novel, validated, and proprietary platform that utilizes the fruit fly Drosophila as a whole animal screening system. Drosophila has played a central role in our understanding of development, and Medros brings this same potential to drug screening. In this Proposal, experiments are described in the laboratories of Drs. Baranski and Cagan that are designed to assess the use of hemolymph ('blood') glucose measurements to further optimize the Drosophila platform. This work will complement work by Medros to screen two libraries- targeting GPCRs and kinases- for lead compounds that suppress the deleterious effects of high glucose on whole Drosophila. Promising compounds, potentially verified by hemolymph glucose measurements, will represent useful leads as Medros enters the diabetes market. [unreadable] [unreadable] [unreadable]